Nghiên cứu đặc điểm lâm sàng, cận lâm sàng và hiệu quả của liệu pháp thay huyết tương trong điều trị viêm tụy cấp do tăng triglycerid máu tt tieng anh

108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES ---DO THANH HOA STUDYING CLINICAL, SUBCLINICAL CHARACTERISTICS AND EFFECTIVENESS OF PLASMA REPLACEMENT THERAPY IN TREATIN

108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

-DO THANH HOA

STUDYING CLINICAL, SUBCLINICAL

CHARACTERISTICS AND EFFECTIVENESS OF PLASMA REPLACEMENT THERAPY IN TREATING

ACUTE PANCREATITIS DUE TO

MEDICAL AND PHARMACEUTICAL SCIENCES

Supervisor:

1 Ass Prof PhD Le Thi Viet Hoa

2 Prof PhD Nguyen Gia Binh

Day Month Year

The thesis can be found at:

1 National Library of Vietnam

2 Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences

BACKGROUND AND OBJECTIVES

Acute pancreatitis (AP) is a sudden onset of pancreatic parenchyma with a mild to a severe course of the disease The consequences may be local lesions, which may cause systemic inflammatory response syndrome and multiple organ failure AP is the leading cause of gastrointestinal diseases requiring hospitalization and 21st in the list of diagnoses requiring hospitalization The mechanism

of AP due to hypertriglyceridemia is thought to be due to the hydrolysis of triglyceride-rich lipoproteins, releasing large amounts of free fatty acids, thereby damaging vascular endothelium and pancreatic islet cells This damage causes ischemia, cytotoxicity, acidosis due to anaerobic metabolism

The treatment of AP due to hypertriglyceridemia, in addition

to general procedures, recently, many studies have demonstrated that plasma exchange (PEX) is a more practical option to lower triglyceride (TG) levels rapidly over a short time This therapeutic is also reducing the length of stay in the hospital and improve patient outcomes To add the scientific basis to evaluate the effectiveness of PEX in the treatment of AP due to hypertriglyceridemia, we conducted the subject: “Studying clinical, subclinical characteristics

and effectiveness of plasma replacement therapy in treating acute pancreatitis due to hypertriglyceridemia" with the following

objectives:

1 Determining clinical features, subclinical, and severity of acute pancreatitis due to hypertriglyceridemia

2 Evaluation of the therapeutic effect and undesirable effects of plasma replacement therapy on patients with acute pancreatitis due

to hypertriglyceridemia

CHAPTER 1 OVERVIEW

1.1 Hypertriglyceridemic pancreatitis

1.1.1 Metabolic Disorders

Hypertriglyceridemia is determined by fasting serum TG level >

150 mg/dL (1.7 mmol/l) TG were classified based on the following level:

Mild (serum TG levels of 150 to 199 mg/dL , or 1.7 to 2.2 mmol/l)

Moderate (200 to 999 mg/dL, or 2.3 to 11.2 mmol/l)

Severe (1000 to 1999 mg/dL, or 11.3 to 2.5 mmol/l)

Very severe (≥2000 mg/dL, or > 22.6 mmol/l)

1.1.3 The pathogenesis of acute pancreatitis due to hypertriglyceridemia

The pathogenesis of AP with increased TG is not clear Recent studies have found that AP due to elevated TG through free fatty acid (FFA) accumulation, activates an inflammatory response, microcirculation disorders, calcium, oxidative stress Hypertriglyceridemic pancreatitis has two main mechanisms: chylomicrons formation and breakdown of TG into free fatty acid in pancreas

1.1.4 Diagnosis of AP cause by hypertriglyceridemia

a Diagnosis of AP

AP is diagnosed according to the Atlanta classification, which requires that two or more of the following criteria: (1) abdominal pain suggestive of pancreatitis (i.e., epigastric abdominal pain may spread

to the back); (2) serum amylase or lipase level greater than three times the upper normal value; (3) characteristic imaging findings on CT, MRI or ultrasound

+ Ultrasound: Full or partial enlargement of the pancreas (head, body, or tail), the ambiguous contour of the pancreas, irregular echo density, reduced volume, or mixed echoes may have peritoneal fluid and abdominal cavity

+ Computerized tomography: Enlarged or normal pancreas, irregular edges, may have necrotic foci, indicating the degree of damage around the pancreas and away from the pancreas

b Diagnosis of AP cause by hypertriglyceridemia

The diagnosis of AP hypertriglyceridemia is determined when clinical and subclinical manifestations of AP are combined with serum TG concentrations > 1000 mg/dL To diagnose AP due to hypertriglyceridemia, necessary to exclude other AP causes: stones, worms

Figure 1.2: Mechanisms involved in the pathophysiology of

hypertriglyceridemic pancreatitis

(Source: Pretis N et al, United European gastroenterology journal)

1.1.5 Criteria for grading the severity of AP

* Revised Atlanta Classification for AP

* Clinical signs of severe AP

* Prognostic signs on laboratory tests and imaging

* The scales to assess prognosis in acute pancreatitis:

 Ranson's criteria is one of the first scoring systems used to assess prognosis in AP

 Glasgow-Imrie Criteria for Severity of AP

 APACHE II score: if ≥ 8 points is severe

 The SOFA (Sequential Organ Failure Assessment) score

 Balthazar computed tomography severity index

1.2 Hypertriglyceridemia-induced acute pancreatitis treatment

1.2.1 General treatment for acute pancreatitis

a Basic resuscitation and medical treatment

- Rapid isotonic infusion 1-2 liters in the first 1-2 hours, then maintain 250-300 ml / kg / 24 hours

- Respiratory: provide oxygen to SpO2> 95%

- Pain relief: NSAIDS or Opi (do not use morphine)

- Antibiotics: when there was evidence of infection

- Nourishment: intravenously for 24-48 hours, then feed by mouth gradually

- Reducing secretion: PPI, sandosatin

b Other interventions

- Continuous dialysis: when AP was severe, multi-organ failure

- Abdominal drainage through the skin: when there was an abdominal fluid in the abdomen

c Treatment of the cause

1.2 2 Treatment for increased triglycerides

The recommendations are agreed that the rapid reduction of

TG level is key in the treatment Following The American Society for Apheresis (ASFA) guidelines: PEX for severe hypertriglyceridemic pancreatitis as 1C grade recommended, PEX in prophylaxis hypertriglyceridemic pancreatitis as 2C grade recommended

1.3 Therapeutic plasma exchange for hypertriglyceridemia induced acute pancreatitis

1.3.1 Technical principles of plasma exchange

Plasma exchange conducted bypassing the blood through an extracellular membrane with a pore size of 0.2 - 0.6 micron (plasma separation filter) - this procedure which allowing plasma proteins to pass through but retain blood cells There are many types of filters: cellulose, polyethylene, polypropylene, and polyvinylchloride

- Acute pancreatitis due to hypertriglyceridemia

- Hypercholesterolemia, Hemolytic uremic syndrome, induced thrombosis (ticlopidine/clopidogrel), systemic lupus

Drug-erythematosus, multiple myeloma with increased blood viscosity or with acute renal failure

1.3.3 Accidents and unwanted effects

- Complications not related to alternative fluids

- Complications related to non-plasma replacement fluids

several hours is equivalent to dropping in a few days when using the drug Besides, PEX can improve the prognosis of AP by eliminating pro-inflammatory factors and cytokines

The data show that PEX in AP patients with hypertriglyceridemia sooner gives better results Numerous studies show that PEX is an effective treatment to quickly reduce blood TG concentrations in AP patients, especially in patients with severe AP risk of complications PEX should be administered as soon as possible, within 24 - 48 hours after the onset of illness and is applied until the TG concentration is <5.6 mmol/l However, PEX is a fairly expensive treatment option and is not available at all centers More randomized controlled studies are needed to assess the effectiveness

of PEX in the treatment of AP hypertriglyceridemia compared to other treatments

CHAPTER 2 SUBJECTS AND METHODS 2.1 Subjects

Patients diagnosed with AP increase TG at the Department of Intensive Care of Bach Mai Hospital from December 2015 to May

- Clinical symptoms: typical abdominal pain (sudden onset, severe pain, concentrated in the epigastric region, spread to back or chest)

- Amylase and or blood lipase increase > 3 times higher than normal values

- Computerized tomography: evidence of acute pancreatitis

b TG test ≥ 11.3 mmol/l (1000 mg/dl) - TG is tested once upon admission and retested after 12 hours

c AP is diagnosed to exclude due to other causes: gallstones, worms from the bile duct, trauma, alcohol

2.1.2 Exclusion criteria

+ Patients <18 years old

+ History of allergy to plasma, albumin, and heparin

+ Contraindications to plasma exchange: consciousness disorders, acute heart failure, myocardial infarction, new unstable cerebral infarction, cerebral hemorrhage, or severe cerebral edema

+ Patients and/or family members did not agree to participate

in the study

+ Patients did not collect enough research data

+ Patients and/or family members want to withdraw from the study

+ Patient died within 24 hours after being admitted to the hospital

2.2 Research methodology

2.2.1 Study design

Cohort descriptive, interventional, comparative research

2.2.2 Sample size and sampling method

2.2.2.1 Sample size: Calculated according to the sample size formula applied to the control study

n = 2 {[(Z(1-α/ 2) + Z(1-β / 2)) x σ] / δ}2

Applying the above formula yields n = 69 patients for each group

In the study, we selected 165 patients diagnosed with hypertriglyceridemic pancreatitis, in which 83 patients treatment using PEX and 82 patients treated according to the guidelines of Vietnam's Ministry of Health in 2015

In the study, we selected 83 patients with AP due to TG gain in PEX and 82 patients with AP due to TG increase without PEX

2.2.2.2 Sampling method: All patients were selected according to the selection and exclusion criteria, were given primary treatment and explained PEX treatment method if there were no contraindications if the family and the patient agreed to conduct PEX will be added to the group with plasma exchange, otherwise were treatment following the

guideline of Vietnam's Ministry of Health

Group 1: Group with plasma exchange (PEX)

Group 2: Non-plasma substituents (without PEX )

2.2.3 Criteria for evaluating research

2.2.3.1 Clinical, subclinical and severity of hypertriglyceridemic pancreatitis at the time of diagnosis

- Clinical characteristics, subclinical characteristics, severity assessment and other parameters

2.2.3.2 The effectiveness of PEX in the treatment of acute pancreatitis due to increased TG

General criteria

- Time of conducting PEX for the first time: from the detection of AP due to increasing TG until using PEX (days), time from entering the department of intensive care to using PEX (hours) The number of PEX filters Use anticoagulants in dialysis: do not use heparin, other anticoagulants Use the lipid-lowering drugs: fibrate, statins The amount of compensated fluids in the first day (ml) Fasting time Use antibiotics Medicine use for vasomotor Respiratory support measures Other support measures: Diuretic, CRRT; Artificial kidney

Evaluate the effectiveness of PEX in the treatment of acute pancreatitis due to increased TG

- Evaluate the level of reduction in TG and cholesterol before and after

the 1st, 2nd, 3rd… of PEX and the 28th day after discharge from the hospital Changes in amylase and lipase, the severity rating scales that assess daily for the first 6 days and discharge from the hospital General treatment results: number of days ' treatment per patient; mechanical ventilation time (days); death rate (patients who die in hospital or discharge from the hospital) Comparing mortality, duration of treatment, duration of mechanical ventilation, fasting time,

in 2 groups with PEX and without PEX

- Comparison of AP complications: Respiratory complications:

pneumonia; ARDS; circulatory complications; Complications kidney

- urinary; multi-organ failure syndrome; AP intra-abdominal lesions: pseudocysts, pancreatic abscess, …

2.2.3.3 Undesirable effects of PEX

Technical errors: coagulation filter, rupture membrane, occlusion catheter, fracture catheter, stamping catheter Immune and allergic complications of PEX: local, systemic, anaphylactic shock

Complications of electrolyte disorders: Increasing or decreasing sodium and blood potassium Infections: systemic, catheter, at the adjacent catheter Bleeding: adjacent catheter bleeding, gastrointestinal bleeding, systemic hemorrhage Other complications: Hypotension in the beginning, hypothermia

2.2.4 Research facilities

Testing machine: Machine AU 2700 Beckman Coulter (USA) Ultrasound machine, computerized tomography machine Dialysis machine: Diapact of B / Braun, Prismaflex of Gambro

2.3 Data processing

Data were entered into the computer using SPSS 22.0 software

Research design diagram

Hypertriglyceridemic pancreatitis

Conventional treatment with rehydration, nutrition and symptoms

The patient is assigned PEX

The patient is assigned PEX

and agrees to perform PEX

Patients with no PEX aspiration

Object 1:Determining clinical features, subclinical and severity of hypertriglyceridemic pancreatitis

Object 2: Evaluation of the therapeutic effect and undesirable effects of

plasma replacement therapy

Conclusions

Recommendations

CHAPTER 3 RESULTS 3.1 General characteristics of the study group

- Average age: 41.0 ± 9.3 years (youngest: 21 years, oldest: 77 years) Male / female ratio = 2.11 / 1 51.8% were overweight, 7.3% were underweight

- 43.6% of patients with acute pancreatitis due to increased triglycerides are related to drinking history 49.7% had previous acute pancreatitis 72.7% had lipid metabolism disorders

3.2 Clinical, subclinical characteristics and severity of hypertriglyceridemic pancreatitis of the study patient group

- The time from the first symptom onset to hospital admission from

1-36 hours, the average is 6.13 ± 5.03 hours Among physical symptoms, abdominal distention was the highest (87.3%)

- There are 29.7% of patients with AP due to hyperglycemia have normal blood amylase test, and 32.1% of patients have normal urine amylase

- There were 56.3% of patients with AP due to hypertriglyceridemia, who had increased blood levels of lipase more than 3 times normal

Table 3.17 The classification of acute pancreatitis according to the

1992 Atlanta and revision in 2007

Groups

Classification

Total (n = 165)

Comment: According to the classification of acute pancreatitis of the

1992 Atlanta and revision in 2007, patients with mild acute pancreatitis accounted for the highest proportion

Figure 3.4 Linear correlation between TG level at admitted to the

hospital and SOFA score

Comments: SOFA score in patients with AP due to increased TG

correlates positively with TG concentration, correlation coefficient r

= 0.35, p <0.05

3.3 Results of general treatment of patients with acute

pancreatitis due to increased triglycerides

3.3.2 General treatment results and complications of AP due to

Group 1 (n = 83) ± SD

Group 2 (n = 82)